Chitosan-functionalized Cu-doped NiO/reduced graphene oxide nanocarrier for pH-triggered delivery of 5-fluorouracil in breast cancer cells.

Breast cancer remains a major contributor to global cancer mortality among women, necessitating the development of biocompatible, stimuli-responsive nanocarriers capable of overcoming the limitations of conventional chemotherapy. Herein, we report a chitosan-functionalized Cu-doped NiO with surface-anchored reduced graphene oxide (Cu:NiO/rGO/CS) as a multifunctional nanocarrier for pH-responsive delivery of 5-fluorouracil (5-FU). The nanoplatform was synthesized via a facile co-precipitation-ultrasonication route, and the individual and synergistic contributions of Cu doping, rGO integration, and chitosan functionalization were systematically evaluated using comparative formulations (NiO/rGO, Cu:NiO/rGO, NiO/rGO/CS). Comprehensive structural, spectroscopic, and morphological analyses confirmed substitutional Cu incorporation, homogeneous rGO anchoring, and uniform chitosan coating with proton-responsive behavior. The Cu:NiO/rGO/CS nanocarrier exhibited near-complete drug release under acidic conditions (97.6% at pH 5.2 within 72 h) while maintaining markedly suppressed release at physiological pH (21.0% at pH 7.4), demonstrating excellent pH selectivity governed by chitosan protonation. Release kinetics followed a concentration-dependent first-order model, indicating diffusion-controlled release regulated by polymer swelling. In vitro evaluation against MCF-7 breast cancer cells revealed significantly enhanced cytotoxicity (IC50 = 35.36 ± 0.275 μg mL-1) and improved intracellular uptake compared with non-functionalized counterparts. Notably, Cu:NiO/rGO/CS surpasses recently reported 5-FU nanocarriers in release efficiency and cytotoxicity, highlighting its competitive advantage. The superior therapeutic performance is attributed to the combined effects of chitosan-mediated pH-responsive gating, rGO-assisted drug affinity, and Cu-induced defect-driven mesoporosity. Collectively, these findings highlight the pivotal role of chitosan functionalization in engineering biologically responsive inorganic‑carbon hybrid nanocarriers, positioning Cu:NiO/rGO/CS as a promising next-generation nanocarrier for targeted breast cancer chemotherapy, enabling controlled release, high drug-loading efficiency, and reduced off-target toxicity.